Elucidation of aggregation mechanism of Alzheimer's β-peptides and development of their aggregation inhibitors
| Project/Area Number |
13460048
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (B)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
Bioproduction chemistry/Bioorganic chemistry
|
|---|
| Research Institution | Kyoto University |
|---|
Principal Investigator |
IRIE Kazuhiro Kyoto Univ., Grad. Sch. Agric, Associate Professor, 農学研究科, 助教授 (00168535)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
SHIMIZU Takahiko Tokyo Metropolitan Institute of Gerontology, Department of molecular Gerontology, Researcher, 分子老化部門, 研究員 (40301791)
|
|---|
| Project Period (FY) |
2001 – 2003
|
| Project Status |
Completed (Fiscal Year 2003)
|
| Budget Amount *help |
¥15,100,000 (Direct Cost: ¥15,100,000)
Fiscal Year 2003: ¥3,700,000 (Direct Cost: ¥3,700,000)
Fiscal Year 2002: ¥3,800,000 (Direct Cost: ¥3,800,000)
Fiscal Year 2001: ¥7,600,000 (Direct Cost: ¥7,600,000)
|
|---|
| Keywords | Alzheimer's disease / Aβ42 / amyloid / β-sheet / turn / familial Alzheimer's disease / βアミロイド / 凝集 / β-sheet / β-turn / 家族性アルツハイマー病 / Aβ1-42 |
|---|
| Research Abstract |
Alzheimer's disease is neuropathologically characterized by the progressive deposition of amyloid in the braid parenchyma and cortical blood vessels. This deposition mainly consists of 40-and 42-mer β-amyloid peptides (Aβ40, Aβ42) which show neurotoxicity and aggregative ability. Cerebral amyloid angiopathy (CAA) in familial Alzheimer's disease is related to missense mutations inside the coding region of these Aβpeptides. In order to clarify the aggregation mechanism of Aβpeptides, all of the variants of Aβ40 and Aβ42 found in CAA were synthesized in a highly pure form and examined for neurotoxicity in PC12 cells and aggregative ability.
All of the Aβ40 mutants at positions 22 and 23 showed stronger neurotoxicity than wild-type Aβ40. Similar tendency was observed for Aβ42 mutants at positions 22 and 23 whose neurotoxicity was 50〜200 times stronger than that of the corresponding Aβ40 mutants, indicating that these Aβ42 mutants are mainly involved in the pathogenesis of CAA. Especially, E
… More
22Q-Aβ42 (Dutch) and E22K-Aβ42 (Italian) aggregated extensively, supporting the clinical evidence that Dutch and Italian patients are diagnosed as hereditary cerebral hemorrhage with amyloidosis. In contrast, A21 G (Flemish) mutation needs alternative explanation with the exception of physicochemical properties of Aβmutants. The FI-IR spectra suggested that aggregation increases theβ-sheet contents of the Aβpeptides. However, turn was also a critical secondary structure for aggregation since residues at positions 22 and 23 that preferably form two-residue β-turn significantly enhanced the aggregative ability.
To identify amino acid residues that are important for the β-sheet formation, a series of proline-substituted mutants of Aβ42 was synthesized and their aggregative ability and neurotoxicity were investigated. Only E22P-Aβ42 extensively aggregated with stronger neurotoxicity than wild-type Aβ42, suggesting that the residues at positions 15〜21 and 24〜32 are involved in the intermolecular β-sheet formation, and that turn formation at positions 22 and 23 plays a crucial role in the aggregation and neurotoxicity of Aβpeptides. These findings become a basis for designing new aggregation inhibitors of Aβpeptides. Less
|
Report
(4 results)
Research Products
(9 results)
